chr2-166288596-C-A

Variant names:

• chr2-166288596-C-A
• rs58465962
• NM_001365536.1:c.1155G>T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001365536.1(SCN9A):​c.1155G>T​(p.Val385Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0108 in 1,611,628 control chromosomes in the GnomAD database, including 754 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.041 (389 hom., cov: 32)
  • Exomes 𝑓: 0.0076 (365 hom.)
• Consequence: SCN9A NM_001365536.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.490

Genes affected

SCN9A (HGNC:10597): (sodium voltage-gated channel alpha subunit 9) This gene encodes a voltage-gated sodium channel which plays a significant role in nociception signaling. Mutations in this gene have been associated with primary erythermalgia, channelopathy-associated insensitivity to pain, and paroxysmal extreme pain disorder. [provided by RefSeq, Aug 2009]

SCN1A-AS1 (HGNC:54069): (SCN1A and SCN9A antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.25).
• BP6: Variant 2-166288596-C-A is Benign according to our data. Variant chr2-166288596-C-A is described in ClinVar as [Benign]. Clinvar id is 130255.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-166288596-C-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.49 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.129 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.1155G>T	p.Val385Val	synonymous_variant	Exon 10 of 27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.1155G>T	p.Val385Val	synonymous_variant	Exon 10 of 27		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.1155G>T	p.Val385Val	synonymous_variant	Exon 10 of 27	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.1155G>T	p.Val385Val	synonymous_variant	Exon 10 of 27	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.1155G>T	p.Val385Val	synonymous_variant	Exon 10 of 27			ENSP00000495983.1
SCN9A	ENST00000454569.6	c.1155G>T	p.Val385Val	synonymous_variant	Exon 10 of 15	1		ENSP00000413212.2
SCN9A	ENST00000452182.2	c.*19G>T		downstream_gene_variant		1		ENSP00000393141.2

Frequencies

GnomAD3 genomes AF: 0.0411 AC: 6245 AN: 152052 Hom.: 389 Cov.: 32

Gnomad AFR AF: 0.132

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0201

Gnomad ASJ AF: 0.0282

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0151

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00347

Gnomad OTH AF: 0.0349

GnomAD3 exomes AF: 0.0150 AC: 3726 AN: 248062 Hom.: 170 AF XY: 0.0138 AC XY: 1857 AN XY: 134570

Gnomad AFR exome AF: 0.136

Gnomad AMR exome AF: 0.00841

Gnomad ASJ exome AF: 0.0356

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.0163

Gnomad FIN exome AF: 0.0000929

Gnomad NFE exome AF: 0.00358

Gnomad OTH exome AF: 0.0131

GnomAD4 exome AF: 0.00765 AC: 11162 AN: 1459460 Hom.: 365 Cov.: 34 AF XY: 0.00776 AC XY: 5633 AN XY: 725944

Gnomad4 AFR exome AF: 0.136

Gnomad4 AMR exome AF: 0.0102

Gnomad4 ASJ exome AF: 0.0369

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0166

Gnomad4 FIN exome AF: 0.000169

Gnomad4 NFE exome AF: 0.00239

Gnomad4 OTH exome AF: 0.0161

GnomAD4 genome AF: 0.0412 AC: 6268 AN: 152168 Hom.: 389 Cov.: 32 AF XY: 0.0396 AC XY: 2949 AN XY: 74398

Gnomad4 AFR AF: 0.132

Gnomad4 AMR AF: 0.0201

Gnomad4 ASJ AF: 0.0282

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.0155

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00347

Gnomad4 OTH AF: 0.0346

Alfa AF: 0.0196 Hom.: 62

Bravo AF: 0.0454

Asia WGS AF: 0.0130 AC: 44 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 10, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

Nov 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary erythromelalgia Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Channelopathy-associated congenital insensitivity to pain, autosomal recessive Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Generalized epilepsy with febrile seizures plus, type 7;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Small fiber neuropathy Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Paroxysmal extreme pain disorder Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.25
CADD	Benign	5.3
DANN	Benign	0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs58465962; hg19: chr2-167145106; COSMIC: COSV104409077; COSMIC: COSV104409077;